1. Field of the Invention
The present invention relates generally to the treatment of fungal infections in mammals. More particularly, the present invention provides methods of treating fungal infections in mammals using pharmaceutical preparations including chelator(s), antifungal agents, and/or monoclonal antibodies. The invention further provides pharmaceutical compositions useful for treating fungal infections.
2. Description of Related Art
Fungi, particularly species of Candida, Aspergillus, and Fusarium are a major cause of infection-related mortality in patients with leukemia and lymphoma. In addition, fungal infection is a major cause of mortality in patients with congenital and acquired deficiencies of the immune system.
For example, several species of Aspergillus are known to cause invasive sinopulmonary infections in seriously immunocompromised patients. Following inhalation of spores, clinical aspergillosis can occur in three major presentations. The first presentation, allergic bronchopulmonary aspergillosis, develops when Aspergillus species colonize the bronchial tree and release antigens that cause a hypersensitivity pneumonitis. The second presentation, aspergilloma or xe2x80x9cfungus ball,xe2x80x9d develops in pulmonary cavities, often in concert with other lung diseases such as tuberculosis. The third form, invasive pulmonary or disseminated aspergillosis, is a life threatening infection with a high mortality rate.
The drug of choice in treatment of invasive aspergillosis, as well as in most other systemic mycoses, is Amphotericin B. Amphotericin B is a polyene antibiotic produced from a strain of Streptomyces nodosus. It is a lipophilic compound which binds to ergosterols in fungal membranes, resulting in the formation of transmembrane channels which allow the escape of metabolites essential to maintaining the viability of the fungal cell. Mammalian cell membranes also contain sterols, and it is believed that this same mechanism of action is responsible for the damaging effects which Amphotericin B is known to exert on mammalian kidney, hematopoietic and central nervous system tissues.
Amphotericin B is not soluble in aqueous solution, and for this reason it is supplied commercially in the form of a colloidal suspension comprising Amphotericin B, desoxycholate, and buffers suspended in a glucose solution. This suspension is usually administered to the patient intravenously over a period of from two to six hours; faster infusions can result in cardiorespiratory arrest. Other possible untoward effects of administering Amphotericin B include fever, nausea and vomiting, diarrhea, renal dysfunction, anemia, hypotension, headache, vertigo, and loss of hearing. Amphotericin B is also available in the form of a phospholipid complex (ABELCET(copyright), e.g.), which offers the advantage of somewhat reduced toxicity for those patients who do not tolerate free Amphotericin B well, although many of the same untoward side effects may be observed in patients receiving this lipid complex form of the drug.
As a consequence of the potential seriousness of its toxic side effects, there is a clear need for an alternative to treating systemic mycoses solely with Amphotericin B and/or other harsh antifungal agents.
The present invention provides an effective method of treating a systemic fungal infection comprising the steps of obtaining a therapeutically effective amount of a pharmaceutical composition comprising at least one chelator, at least one antifungal agent and a pharmaceutical excipient, diluent or adjuvant, and administering said pharmaceutical composition to a patient having a fungal infection.
For the purposes of this disclosure, the phrase xe2x80x9ctherapeutically effective amountxe2x80x9d is defined as a dosage sufficient to induce a fungicidal or fungistatic effect upon fungi contacted by the composition. That amount of the pharmaceutical composition which is therapeutically effective will depend upon the ingredients comprising the composition, as well as the treatment goals.
For the purposes of this disclosure, the phrase xe2x80x9ca chelatorxe2x80x9d denotes one or more chelators. As used herein, the term xe2x80x9cchelatorxe2x80x9d is defined as a molecule comprising nonmetal atoms, two or more of which atoms are capable of linking or binding with a metal ion to form a heterocyclic ring including the metal ion.
For the purposes of this disclosure, the phrase xe2x80x9can antifungal agentxe2x80x9d denotes one or more antifingal agents. As used herein, the term xe2x80x9cantifungal agentxe2x80x9d is defined as a compound having either a fungicidal or fungistatic effect upon fungi contacted by the compound.
As used herein, the term xe2x80x9cfungicidalxe2x80x9d is defined to mean having a destructive killing action upon fungi. As used herein, the term xe2x80x9cfungistaticxe2x80x9d is defined to mean having an inhibiting action upon the growth of fungi.
As used herein the terms xe2x80x9ccontactxe2x80x9d, xe2x80x9ccontactedxe2x80x9d, and xe2x80x9ccontactingxe2x80x9d, are used to describe the process by which a pharmacological agent, e.g., any of the compositions disclosed in the present invention, comes in direct juxtaposition with the target cell.
Preferable chelators for use in the present invention include, but are not limited to, ethylenediamine-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid (EDTA); the disodiurn, trisodium, tetrasodium, dipotassium, tripotassiun, dilithium and diammonium salts of EDTA; the barium, calcium, cobalt, copper, dysprosium, europium, iron, indium, lanthanum, magnesium, manganese, nickel, samarium, strontium, and zinc chelates of EDTA; trans-1,2-diaminocyclohexane-N,N,Nxe2x80x2,Nxe2x80x2-tetraaceticacid monohydrate; N,N-bis(2-hydroxyethyl)glycine; 1,3-diamino-2-hydroxypropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; 1,3-diaminopropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; ethylenediamine-N,Nxe2x80x2-diacetic acid; ethylenediamine-N,Nxe2x80x2-dipropionic acid dihydrochloride; ethylenediamine-N,Nxe2x80x2-bis(methylenephosphonic acid)hemihydrate; N-(2-hydroxyethyl)ethylenediamine-N,Nxe2x80x2,Nxe2x80x2-triacetic acid; ethylenediamine-N,N,Nxe2x80x2,Nxe2x80x2-tetrakis(methylenephosponic acid); O,Oxe2x80x2-bis(2-aminoethyl)ethyleneglycol-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; N,N-bis(2-hydroxybenzyl)ethylene diamine-N,N-diacetic acid; 1,6-hexamethylenediamine-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; N-(2-hydroxyethyl)iminodiacetic acid; iminodiacetic acid; 1,2-diaminopropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; nitrilotriacetic acid; nitrilotripropionic acid; the trisodium salt of nitrilotris(methylenephosphoric acid); 7,19,30-trioxa-1,4,10,13,16,22,27,33-octaazabicyclo[11,11,11]pentatriacontane hexahydrobromide; and triethylenetetraminie-N,N,Nxe2x80x2,Nxe2x80x3,Nxe2x80x2xe2x80x3,Nxe2x80x2xe2x80x3-hexaacetic acid. It is contemplated that any chelator which binds barium, calcium, cerium, cobalt, copper, iron, magnesium, manganese, nickel, strontiurn, or zinc will be acceptable for use in the present invention.
More preferably, the chelators for use in conjunction with the present invention may include ethylenediarnine-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid (EDTA); the disodium, trisodium, tetrasodium, dipotassium, tripotassium, dilithium and diammonium salts of EDTA; 1,3-diamino-2-hydroxypropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; 1,3-diaminopropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; O,Oxe2x80x2-bis(2-aminoethyl)ethyleneglycol-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; and 7,19,30-trioxa-1,4,10,13,16,22,27,33-octatazbicyclo[11,11,11]pentatriacontane hexahydrobromide.
Most preferably, the chelators for use in the present invention may include ethylenediamine-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid (EDTA); the disodium salt of EDTA; 1,3-diaminopropane-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid; and O,Oxe2x80x2-bis(2-aminoethyl)ethyleneglycol-N,N,Nxe2x80x2,Nxe2x80x2-tetraacetic acid.
Many antifungal agents are known to those of skill in the art and may be useful in the present invention. For example, antifungal agents contemplated for use in the present invention include, but are not limited to, new third generation triazoles such as UK 109,496 (Voriconazole); SCH 56592; ER30346; UK 9746; UK 9751; T 8581; and Flutrimazole; cell wall active cyclic lipopeptides such as Cilofingin LY121019; LY303366 (Echinocandin); and L-743872 (Pneurnocandin); allylamines such as Terbinafine; imidazolees such as Omoconazole, Ketoconazole, Terconazole, Econazole, Itraconazole and Fluconazole; polyenes such as Amphotericin B, Nystatin, Natamycin, Liposomal Amphotericin B, and Liposomal Nystatin; and other antifungal agents including Griseofulvin; BF-796; MTCH 24; BTG-137586; RMP-7/Amphotericin B; Pradimicins (MNS 18184); Benanomicin; Ambisome; ABLC; ABCD; Nikkomycin Z; and Flucytosine.
More preferably, the antifungal agents for use in conjunction with the present invention may include polyenes such as Amphotericin B, Nystatin, Natamycin, Liposomal Amphotericin B, and Liposomal Nystatin; cell wall active cyclic lipopeptides such as Cilofungin LY121019; LY303366 (Echinocandin); and L-743872 (Pneurnocandin); and other antifungal agents including Griseofulvin and Flucytosine.
Most preferably, the antifungal agents for use in the present invention may include Amphotericin B, Nystatin, Liposomal Amphotericin B, and Liposomal Nystatin.
The present invention also provides an effective method of treating a systemic fungal infection comprising the steps of obtaining a therapeutically effective amount of a pharmaceutical composition comprising at least one chelator operatively attached to a monoclonal antibody, at least one antifungal agent and a pharmaceutical excipient, diluent or adjuvant, and administering said pharmaceutical composition to a patient having a fungal infection. The monoclonal antibody is chosen to bind to a specific fungal antigen, and may be prepared according to any known method. The chelators and antifingal agents may be chosen from those indicated above.
Monoclonal antibodies useful in conjunction with the present invention are those that are specific for a targeted species of fungus. In preferred embodiments, the monoclonal antibodies are operatively attached to chelators. For the purposes of this disclosure, the phrase xe2x80x9ca monoclonal antibodyxe2x80x9d denotes one or more monoclonal antibodies. As used herein, the term xe2x80x9cmonoclonal antibodyxe2x80x9d is defined as an antibody derived from a single clone of a B lymphocyte. Furthermore, as used herein, the term xe2x80x9coperatively attachedxe2x80x9d connotes a chemical bond, either covalent or ionic, between the monoclonal antibody and chelator. As used herein, the term xe2x80x9cspecificxe2x80x9d indicates that a chemical site on the monoclonal antibody will recognize and bind with a complementary chemical site on the surface of the cell of at least the fungal pathogen of interest.
The pharmaceutical compositions of the invention are provided to a patient having a fungal infection in an amount sufficient to exert a fungicidal or fungistatic effect upon fungi contacted by the composition. It will be understood with benefit of this disclosure that such dosages may vary considerably according to the patient, the infection presented by the patient, and the particular active ingredients comprising the pharmaceutical composition.
The antifungal agents of the present invention may be administered to a patient in an amount ranging from about 0.001 milligrams per kilogram of body weight per day to about 1000 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.001, 0.002, 0.003, etc.; 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 100, 101, 102, 103, 104, etc.; 500, 501, 502, 503, etc.; 600, 700, 800, 900, and about 1000 mg per kg per day, and including all fractional dosages therebetween.
More preferably, the antifungal agents of the present invention may be administered to a patient in an amount ranging from about 0.01 milligrams per kilogram of body weight per day to about 100 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 60, 70, 80, 90, and about 100 mg per kg per day, and including all fractional dosages therebetween.
Most preferably, the antifungal agents of the present invention may be administered to a patient in an amount ranging from about 0.1 milligrams per kilogram of body weight per day to about 10 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9 and about 10 mg per kg per day, and including all fractional dosages therebetween.
The chelators of the present invention may be administered to a patient in an amount ranging from about 0.001 milligrams per kilogram of body weight per day to about 1000 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.001, 0.002, 0.003, etc.; 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 100, 101, 102, 103, 104, etc.; 500, 501, 502, 503, etc.; 600, 700, 800, 900, and about 1000 mg per kg per day, and including all fractional dosages therebetween.
More preferably the chelators of the present invention may be administered to a patient in an amount ranging from about 0.01 milligrams per kilogram of body weight per day to about 100 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 60, 70, 80, 90, and about 100 mg per kg per day, and including all fractional dosages therebetween.
Most preferably the chelators of the present invention may be administered to a patient in an amount ranging from about 0.1 milligrams per kilogram of body weight per day to about 10 mg per. kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9; and about 10 mg per kg per day, and including all fractional dosages therebetween.
The monoclonal antibodies operatively attached to chelators may be administered to a patient in an amount ranging from about 0.001 milligrams per kilogram of body weight per day to about 1000 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.001, 0.002, 0.003, etc.; 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 100, 101, 102, 103, 104, etc.; 500, 501, 502, 503, etc.; 600, 700, 800, 900, and about 1000 mg per kg per day, and including all fractional dosages therebetween.
More preferably, the monoclonal antibodies operatively attached to chelators may be administered to a patient in an amount ranging from about 0.01 milligrams per kilogram of body weight per day to about 100 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.01, 0.02, 0.03, etc.; 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, 10, etc.; 12, 13, 14, etc.; 50, 51, 52, 53, 54, etc.; 60, 70, 80, 90, and about 100 mg per kg per day, and including all fractional dosages therebetween.
Most preferably, the monoclonal antibodies operatively attached to chelators may be administered to a patient in an amount ranging from about 0.1 milligrams per kilogram of body weight per day to about 10 mg per kg per day, including all intermediate dosages therebetween. It will be readily understood that xe2x80x9cintermediate dosagesxe2x80x9d, in these contexts, means any dosages between the quoted ranges, such as about 0.1. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, etc.; 3, 4, 5, 6, 7, 8, 9, and about 10, and including all fractional dosages therebetween.
The pharmaceutical compositions of the present invention may be administered by any known route, including parenterally and otherwise. This includes oral, nasal (via nasal spray or nasal inhaler), buccal, rectal, vaginal or topical administration. Administration may also be by orthotopic, intradermal subcutaneous, intramuscular, intraperitoneal or intravenous injection and/or infusion. Such compositions may be administered as pharmaceutically acceptable compositions that include pharmacologically acceptable carriers, buffers or other excipients. The phrase xe2x80x9cpharmacologically acceptablexe2x80x9d refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a human. For treatment of conditions of the lungs, the preferred route is aerosol delivery to the lung via bronchoalveolar lavage or the like.
When administration of the pharmaceutical compositions of the present invention via intravenous injection and/or infusion is the preferred route, the pharmaceutical compositions of the present invention should administered gradually over a period of time ranging from 0.001 h to 100 h. More preferably, when administration of the pharmaceutical compositions of the present invention via intravenous injection and/or infusion is the preferred route, the pharmaceutical compositions of the present invention should administered gradually over a period of time ranging from 0.1 h to 50 h. Most preferably, when administration of the pharmaceutical compositions of the present invention via intravenous injection and/or infusion is the preferred route, the pharmaceutical compositions of the present invention should administered gradually over a period of time ranging from 1 h to 10 h.